What's Up, Doc? Genetic diseases affect patients differently

Q: A 40-year-old lady just moved in next door, and she is in a wheelchair. She told me she had SMA, which is a kind of muscular dystrophy. I thought only boys got muscular dystrophy. What is SMA?

Dr. Jeff Hersh

Q: A 40-year-old lady just moved in next door, and she is in a wheelchair. She told me she had SMA, which is a kind of muscular dystrophy. I thought only boys got muscular dystrophy. What is SMA?

A: You must be thinking of Duchenne muscular dystrophy, which is an X-linked recessive disease. Recessive means you only get the disorder if you do not have any ``normal'' (unaffected) copies of the gene; so you either need to get two copies of an affected gene or one affected sex-linked gene for boys (since boys have only one X and one Y gene).

Girls have two X chromosomes so they can be carriers of Duchenne's but will not get the disorder; they will get a non-affected copy of the X chromosome from their dad along with a 50 percent chance of being carriers from getting an affected X chromosome from their mom (I will not discuss cases where a baby girl has some other genetic disorder). Boys get the Y chromosome from their dad, so if their mom is a carrier they have a 50 percent chance of getting the affected X chromosome from their mom.

SMA, which your new neighbor has, stands for spinal muscular atrophy. Like Duchenne muscular dystrophy it is also a recessive-inherited disorder that affects the muscles, but unlike Duchenne muscular dystrophy it is not linked to the sex genes (X or Y genes). (Actually one subtype of SMA - spinal-bulbar muscular atrophy - is X-linked, but I will not discuss this in today's column.)

Doctors Guido Werdnig and Johann Hoffman first described SMA in the 1890s. It is an uncommon disease, affecting 1 in 6,000 to 15,000 people. Note that this is not much different than the incidence of many more familiar diseases such as cystic fibrosis (1 in 1,700 to 6,500 Caucasian babies), Duchenne muscular dystrophy (1 in 4,000 males) or sickle cell (1 in 500 African American births). Although this is not the most common inherited disorder, it can be rapidly fatal in some cases (see discussion below) and it is the No. 1 genetic disorder that causes death before age 2.

As noted, SMA is inherited in a recessive manner so to get the disease both parents must be carriers of an affected gene (then there is a 25 percent chance the baby will have the disease); it is estimated that 1 in 40 people are carriers of this disease.

SMA occurs because the baby is born with a missing or mutated SMN1 (survival motor neuron 1) gene. People without this gene cannot make a protein that enables the nerve cells that control the muscles to work and survive normally. Without these nerves to stimulate the muscles they weaken and then atrophy.

SMA manifests not only in muscle weakness, but often also in deformities of some of the bones since the push and pull balance the muscles exert on the bones is altered by the disease. When the muscles that help you breath become compromised, there is an increased risk of pneumonia. Sensation is not affected by this condition since only the motor nerves are affected and SMA does not affect intellect.

The more severely the baby is affected, the earlier they develop symptoms and the worse their prognosis. Since the developmental milestones the baby fails to reach as they grow define the four subtypes of SMA, it is useful to quickly review normal baby development. It is important to realize that these milestones are guidelines, and every child is different. This is why it is so important for a baby to get all those checkups from their healthcare provider.

Normal milestones

Birth to 2 months: babies move their head from side to side, bring their hands to their face and make jerky movements with their arms
1 to 3 months: briefly lift their head while on their tummy
2 to 3 months: lift their head 45 degrees and support their bodies with their arms while on their tummy
2 to 5 months: roll over from tummy to back, grab with their hands
4 to 6 months: lift their heads up, arch their backs, lift their chests off the ground
4 to 7 months: bear some weight on their legs while you hold them up
5 to 7 months: roll over back to tummy and tummy to back, play peek-a-boo
4 to 10 months: sit up without your support
6 to 12 months: crawl
8 to 12 months: pull themselves up and walk while holding onto furniture (cruises)
10 to 18 months: walk
2 years: kick a large ball
3 years: walk up stairs, feed themselves, stand briefly on one foot, ride a tricycle
4 years: hop in place, throw a ball over head
5 years: walk backward heel-toe

With this knowledge we can now discuss the subtypes of SMA. Type 1 SMA is also called Werdnig-Hoffman disease. These babies are affected before they are 6 months of age and miss the milestones for this age. They usually do not develop appropriate head control and, typically, are never able to sit up on their own or walk. These babies will usually have trouble swallowing and eventually develop trouble breathing due to weakness of the breathing muscles. This is the most severe form of SMA and half of these babies will die before age 2.

Type 2 SMA affects babies between age 6 and 18 months. They may be late on some of the milestones for these ages, but are able to sit on their own and some can even stand without support. They get pneumonia more easily since their breathing muscles are somewhat weakened. They may also have pronounced curvature of the spine from the weakness and imbalance of the muscles of the back.

Type 3 is also called Kugelberg-Welander disease and is the mildest of the childhood-onset SMAs. It begins to cause symptoms between ages 18 months and adolescence. Although these children can walk, they clearly become weak and they may fall more often than other kids and not be able to run. Some may need to use their arms to push on their legs to help them rise from a chair. Most of these kids eventually need a wheelchair.

Type 4 is the mildest form of SMA and symptoms begin in adulthood, usually in a patient's 30s. It is thought to be the least common type of SMA, although its insidious onset and slow progression may make this type of SMA under-diagnosed. As with the other types of SMA the proximal muscles - those closer to the trunk; the shoulder and hip muscles - are usually affected first.

There is no cure for SMA, but there are treatments to minimize complications from this inherited disorder. This includes respiratory support for those babies whose breathing is compromised, as well as nutritional support (such as a tube to their stomachs) for those babies that cannot swallow sufficiently to get adequate nutrition. For those with milder symptoms from the disease (later onset) but whose spines become curved, surgery to help straighten the spine may be needed (a severely curved spine can make breathing even more difficult).

Patients with SMA may benefit from physical therapy to minimize joint stiffness and to maintain flexibility. This may include exercise programs (possibly while in a warm tub), as well as occupational therapy to teach them techniques to continue with routine daily requirements despite their disability.

The suspicion of SMA will arise from the patient's symptoms of weakness and/or missed developmental milestones, and the disorder will be confirmed by tests that can be done. Genetic testing for this condition is done from a blood test to check for the absence of the SMN1 gene. Other testing may be done to evaluate for other disorders that can cause similar symptoms. Your healthcare provider will discuss what tests may be needed. For those families that have a child with SMA, genetic counseling should be done so they understand the risks of future children inheriting the condition. For those parents that feel it is appropriate, prenatal testing is also available.

There is active and ongoing research for SMA, and there are a couple of clinical trials underway looking to see if certain medications and treatments can help patients with this disorder. Patients and families affected by SMA should discuss these with their healthcare provider. For more information, visit www.ProjectCureSMA.org or the Families of SMA Web site at www.fsma.org.